Effects of amphetamine on brain protein synthesis and energy metabolism are investigated in mice under conditions which give rise to changes in body temperature in response to the drug. Protein synthesis is assayed by an in vitro amino acid incorporation method developed in the laboratory to replace polyribosome profiles. Glycogen, glucose, phosphocreative, and adenine and guanine nucleotides are measured enzymatically. During a period of drug induced hyperthermia, the inhibition of brain protein synthesis is tightly correlated with body temperature, inhibition occurring abruptly between 40 and 41 C. Brain glycogenolysis induced by the drug is more pronounced at elevated ambient temperatures, but does not correlate well with temperatures of individual mice. Through these and other observations, the reduction in brain protein synthesis by amphetamine can largely be dissociated from its effects on energy metabolism. Further studies will examine the possible activation of a translational inhibitor in extracts of hyperthermic animals.